December 6, 2016
Stefan Zeuzem, M.D., presenting study results (Credit: Warren Tong)
A fixed-dose combination of sofosbuvir (SOF, Sovaldi), velpatasvir (VEL) and voxilaprevir (VOX) yielded a 97% sustained virologic response rate 12 weeks after treatment ended (SVR12) in patients with direct-acting antiviral (DAA) experience but still naive to NS5A inhibitors. Fixed-dose SOF/VEL (Epclusa) resulted in a 90% SVR12 in the randomized, active-comparator POLARIS-4 trial.
POLARIS-4 investigators noted that a small proportion of hepatitis (HCV) patients do not achieve SVR with their first DAA regimen. They conducted this trial to test two options for patients with DAA experience -- the fixed-dose combination SOF/VEL/VOX and the fixed-dose combination SOF/VEL. SOF is a pangenotypic inhibitor of the HCV NS5B protein, VEL a pangenotypic inhibitor of NS5A and VOX a pangenotypic inhibitor of NS3/4A protease. Participants had DAA experience, but the trial excluded those who had taken an NS5A inhibitor or an NS3/4A inhibitor plus ribavirin (Rebetol) and pegylated interferon.
This open-label trial at 102 sites in North America, Europe, Australia and New Zealand randomized HCV genotype 1, 2 or 3 patients equally to 12 weeks of SOF/VEL/VOX or SOF/VEL, while participants with other genotypes all received SOF/VEL/VOX. The primary endpoint was SVR12, and an efficacy analysis rated each regimen against a prespecified performance goal of 85% at a P value of .025.
Of the 182 participants who started SOF/VEL/VOX and the 151 who started SOF/VEL, age averaged 57 years, about three-quarters were men, 88% were white, 46% had cirrhosis and pretreatment viral load averaged 6.3 log10 IU/mL. In the SOF/VEL/VOX and SOF/VEL groups, respectively, 43% and 43% had genotype 1, 17% and 22% had genotype 2 and 30% and 34% had genotype 3. While 69% of participants had already taken SOF, 11% had taken SOF plus simeprevir (Olysio). All 182 participants who started SOF/VEL/VOX completed treatment, while 149 of 151 who started SOF/VEL completed therapy.
Of the 182 people in the SOF/VEL/VOX arm, 177 (97%) achieved SVR12. Among the five who did not, one relapsed, one died and three were lost to follow-up. Of the 151 in the SOF/VEL arm, 136 (90%) achieved SVR12. Among the 15 who did not, there were 14 relapses and one breakthrough. The performance analysis determined that SOF/VEL/VOX was superior to the prespecified 85% SVR12 goal (P < .001), while SOF/VEL was not (P = .092).
SVR12s with SOF/VEL/VOX and SOF/VEL were 98% and 94% for patients without cirrhosis and 96% and 86% for those with cirrhosis, respectively. Respective SVR12s were 98% and 89% for genotype 1a, 96% and 95% for genotype 1b, 100% and 97% for genotype 2, 94% and 85% for genotype 3 and 100% with SOF/VEL/VOX for genotype 4. With SOF/VEL/VOX, SVR12 was 94% or higher regardless of baseline resistance-associated substitutions. With SOF/VEL, SVR12 was 90% with any resistance-associated substitution and 50% (two of four patients) with NS3 plus NS5A resistance-associated substitutions.
Two participants in each study arm had a grade 3 or 4 adverse event, no one had a drug-related serious adverse event and one person taking SOF/VEL stopped treatment because of an adverse event (headache). Rates of grade 3 lab abnormalities were 5% with SOF/VEL/VOX and 6% with SOF/VEL. One person in each group had a grade 4 lab abnormality. Approximately one-quarter of participants in each study arm reported headache and one-quarter reported fatigue. Diarrhea affected 20% taking SOF/VEL/VOX (86% grade 1).
The POLARIS-4 investigators concluded that "SOF/VEL/VOX for 12 weeks is a highly effective salvage therapy" for DAA-experienced patients who have not taken an NS5A inhibitor.
Mark Mascolini writes about HIV and hepatitis virus infection.
Copyright © 2016 Remedy Health Media, LLC. All rights reserved.
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